Wider Look at Lung Cancer Genes Found Helpful

Action Points

Testing for a range of genetic drivers of lung cancer broader than the current standard pointed to actionable treatment targets for most patients, which was linked to survival.

Note that the most common mutations found were the Big Three already routinely checked in clinical practice -- KRAS (25%), sensitizing EGFR (21%), and ALK rearrangements (8%).

Testing for a range of genetic drivers of lung cancer broader than the current standard pointed to actionable treatment targets for most patients, which were linked to survival, a study showed.

Simultaneously genotyping for a panel of 10 genes turned up oncogenic drivers in 64% of metastatic lung adenocarcinoma patients, Mark G. Kris, MD, of Memorial Sloan Kettering Cancer in New York City, and colleagues found.

The most common were the Big Three already routinely checked in clinical practice -- KRAS (25%), sensitizing EGFR (21%), and ALK rearrangements (8%), the group reported in the May 21 issue of the Journal of the American Medical Association.

But that still left one in 10 patients with actionable information that would not have been found by looking for only those.

"Actionable" didn't necessarily mean they have a proven targeted drug yet, but there's reason to expect that these will become important to treatment, commented Jeffrey Kern, MD, director of the Lung Cancer Center at National Jewish Health in Denver.

"If you only did the standard ones -- KRAS, EGFR, and ALK -- if those were negative, you're really potentially missing out on the opportunity to identify another mutation for which you may not have a commercially-available drug but could direct someone to molecular-targeted therapy to understand what the effect is and potentially give them a better response," he noted.

At the beginning of the study, the only mutation-targeted therapies available were the EGFR tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva), though more were on the horizon.

Now crizotinib (Xalkori) is available to target ALK rearrangements. KRAS mutations point to patients likely to be resistant to erlotinib and gefitinib.

The research group initiated clinical trials for therapeutic agents targeting nine of the 10 drivers, so patients had an opportunity to get treatment based on the rarer mutations.

Those included other EGFR mutations in 4% of patients; ERBB2 (formerly HER2) in 3%; BRAF in 2%; and PIK3CA, MET amplification, NRAS, and MEK1 in less than 1% each.

The genotyping panel also included AKT1, but it wasn't found in any of the 733 patients tested with it.

Altogether, the genotyping information was used to select a targeted therapy or trial in 275 of the total 1,007 patients (28%).

The results also supported an apparent survival advantage to doing so.

Median survival was 3.5 years for the 190 patients with an identified oncogenic driver for their tumor that was then treated with genotype-directed therapy, compared with 2.4 years with an identified oncogenic driver not targeted for treatment.

However, "randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival," Kris and colleagues cautioned.

An accompanying editorial pointed out that the mutations likely impact tumor biology in ways linked to survival, aside from just providing a treatment target.

The survival looked even better for the 49 patients with oncogenic drivers other than EGFR or ALK who also received a targeted therapy (median 4.9 years).

"Despite the small number of patients, however, these findings provide a strong rationale for the study of additional targeted therapies in lung adenocarcinoma," wrote Boris Pasche, MD, PhD, of Wake Forest University in Winston-Salem, N.C., and Stefan C. Grant, MD, JD, MBA, of the University of Alabama at Birmingham.

The findings also have implications for clinical trial design, their editorial suggested.

"Clearly, these findings demonstrate the feasibility of prospectively incorporating genomic testing into clinical trial designs and, if effective, into clinical care," they noted.

The study's proof of principle should be a starting point for "a new clinical trial model employing large multicenter clinical trials offering experimental treatment for multiple targets," Pasche and Grant added.

It would be a new level of collaboration for all stakeholders but the most efficient way to develop novel treatments for rare but targetable oncogenic drivers, they explained.

The study included 1,007 patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 at 14 U.S. sites; they were genotyped from 2009 through 2012 (733 had enough tumor material to test for all 10 genes).

Altogether, 3% of patients harbored two or more genes considered an actionable oncogenic driver.

"This is going to change what we do; it's a matter of the scope of the change," Kern said, noting that some centers are moving beyond what was done in the trial to next-generation sequencing of a much larger panel of genes.

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